Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder

Abstract

SUMMARY Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ~24 hour rhythms in many behavioral and physiological processes. This system is altered in Delayed Sleep Phase Disorder (DSPD), a common form of insomnia where sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6% and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.

Time Travels: A 40‐Year Journey from Drosophila's Clock Mutants to Human Circadian Disorders (Nobel Lecture)

“…Both genes restored circadian rhythms in the otherwise arrhythmic cultured cells.The CRY1 variant, however,p roduced rhythms that were long-period (Patke et al,2 017). [22] This change was also seen when both versions of CRY1 were simultaneously expressed in the cells. Thus,t he mutation associated with DSPD was capable of producing ad ominant change in the circadian rhythm of the recipient cells that was consistent with the effects on wake sleep behavior in the DSPD subjects.…”

“…Figure 5s hows records of the patterns of sleep for two individuals that were part of aD SPD study we began an umber of years ago (Patke et al,2 017). [22] Figure 5A presents the record for acontrol subject and 5B for asubject diagnosed with DSPD.T he records show results of two kinds of monitoring. One involves collection of data from aw ristwatch-like activity monitor.…”

“…Thep roband is heterozygous and produces two forms of CRY1 RNAand protein with the predicted sizes (Patke et al, 2017). [22] We next asked whether the variant CRY1 gene altered features of circadian rhythmicity in an unrelated line of cultured cells.S tarting with cultured mouse cells that were deficient for both mammalian Cryptochrome genes (CRY1 and CRY2), we alternatively transfected with aw ildtype or the mutant form of CRY1. Both genes restored circadian rhythms in the otherwise arrhythmic cultured cells.The CRY1 variant, however,p roduced rhythms that were long-period (Patke et al,2 017).…”

“…In contrast, no such bias was observed in following interactions between CRY1 and PER. These findings suggest that the basis for dominance of the tau11 form of CRY1 reflects the prefer-ential involvement of the tau11 form in function of the circadian clock in heterozygotes.W ea lso found that cells expressing CRY1-tau11 produced lower levels of CRY1 and PER RNA, indicating that CRY1/PER complexes were strengthened transcriptional inhibitors (Patke et al,2017). [22] As earch for the tau11 CRY1 variant in several publicly addressable DNAs equence databases indicated that this allele (rs184039278/CRY1 c.1657 + 3A > C) has ac arrier frequency of % 1% among those with European ancestries (Patke et al,2 017).…”

“…These findings suggest that the basis for dominance of the tau11 form of CRY1 reflects the prefer-ential involvement of the tau11 form in function of the circadian clock in heterozygotes.W ea lso found that cells expressing CRY1-tau11 produced lower levels of CRY1 and PER RNA, indicating that CRY1/PER complexes were strengthened transcriptional inhibitors (Patke et al,2017). [22] As earch for the tau11 CRY1 variant in several publicly addressable DNAs equence databases indicated that this allele (rs184039278/CRY1 c.1657 + 3A > C) has ac arrier frequency of % 1% among those with European ancestries (Patke et al,2 017). [22] This suggested that we should be able to identify additional carriers to further test the association of the allele and DSPD.Inacollaboration with Tayfun ÖzÅelik at Bilkent University in Tu rkey,s everal Middle Eastern families with both homozygous and heterozygous carriers, were recognized.…”